Innovative Therapies and Clinical Studies for Classic Galactosemia

描述（由申请人提供）：在人类中，由GALT基因突变引起的半乳糖-1-磷酸尿苷转移酶（GALT）缺乏会导致一种潜在的致命疾病，即经典的半乳糖血症。如果患病婴儿在出生后5至9天内不从饮食中停用半乳糖，一些新生儿会死于肝功能衰竭和大肠杆菌败血症。尽管美国所有50个州都将这种代谢紊乱纳入新生儿筛查项目，并且半乳糖限制饮食可以预防一些受影响婴儿的新生儿死亡，但许多存活下来的患者出现了使人衰弱的并发症，包括生长受限、卵巢早衰、语言运动障碍、共济失调和其他神经功能缺陷。该项目的长期目标是为经典半乳糖血症患者开发更有效的治疗方法。

DESCRIPTION (provided by applicant): In humans, deficiency of galactose-1-phosphate uridyltransferase (GALT) caused by mutations in the GALT gene leads to a potentially lethal disease, classic galactosemia. If galactose is not withdrawn from the diet of affected infants within five to nince days of life, some newborns die of hepatic failure and Escherichia coli sepsis. Although all 50 states in the U.S. include this metabolic disorder in newborn screening programs and a galactose-restricted diet prevents neonatal death in some affected infants, many surviving patients develop debilitating complications including growth restriction, premature ovarian failure, speech dyspraxia, ataxia, and other neurological deficits. The long-term goal of this project is to develop more effective therapies for patients with classic galactosemia. Earlier, the investigators defined the structure-function basis of specific GALT mutations and established genotype-phenotype relationships for disease severity and outcome. Using patient cells that are homozygous for the Q188R-GALT mutation, they recently showed that galactose insult to these cells resulted in accumulation of galactose-1-phosphate (Gal-1-P) and manifestation of endoplasmic reticulum (ER) stress prior to cell death. Through serendipity, they also discovered that supplementation of specific antioxidants protected these cells from galactose toxicity. They hypothesize that patient genotypes, which dictate the amount of Gal-1-P accumulated, define the degree of cellular toxicity via mechanisms involving ER stress and oxidative stress. To test this hypothesis, the investigators propose, in Specific Aim 1, to derive diploid fibroblast cells strains from galactosemic patients homozygous for three different mutant alleles: Q188R, S135L, and ?5kb. They will characterize these cell strains and use them to test the efficacies of novel therapies; in Specific Aim 2, to discover small molecule inhibitors for human galactokinase (GALK), the enzyme responsible for the production of Gal-1-P, and to test their efficacy in preventing ER stress in GALT-deficient cells stratified by genotypes; and in Specific Aim 3, to delineate the molecular mechanisms by which antioxidant supplementation protects GALT-deficient cells from galactose toxicity, stratified by genotype.